1. Field of the Invention
This invention relates to a general process for producing N-arylated compounds having at least one unsaturated nitrogen atom, and more particularly to a general process for the formation of N-arylated compounds from azoles or imines, and an arylating compound using a transition metal catalyst.
2. Description of the Art
N-Aryl azoles are important substructures in natural products and industrial chemicals, such as pharmaceuticals, dyes, and agricultural products. N-Aryl azoles such as N-aryl pyrrole, N-aryl carbazole, and N-aryl indole, display a variety of biological activity such as antimicrobial activity (Kamat et al., Ind. J. Chem., 33B:255-259 (1994)), dopamine D-2 and serotonin 5-HT2 antagonist activity (Perrgaard et al., J. Med. Chem. 35:1092-1101 (1992)); analgesic activity (Glamkowski et al., J. Med. Chem. 28:66-73 (1985) and antiallergy activity (Unangst et al., J. Med. Chem. 32:1360-1366 (1989)). N-Aryl imines, on the other hand, are protected anilines (Greene et al., Protective Groups in Organic Synthesis; John Wiley and Sons, Inc., New York, 1991) which are useful in the synthesis of pharmaceuticals, polymers and oligomers.
It would be advantageous to prepare N-aryl azoles and N-aryl imines from arylating compounds such as aryl halides and/or aryl sulfonates because aryl halides are generally inexpensive and readily available, while aryl sulfonates are easily prepared from phenols. However, to date, methods of producing N-aryl azoles an imines are inefficient or economically unattractive. In one example, the phenylation of azoles with electrophilic aromatic main group compounds produce N-aryl azoles as one of several aryl compounds in the resulting product mixture (Lopez-Alvarado et al., J. Org. Chem. 60:5678 (1995); Barton et al., Tetrahedron Lett. 27:3615-3618 (1986)). Complex purification steps are therefore required to isolate the desired compounds if this production method is used.
In another example, potassium fluoride adsorbed onto alumina mediates arylations of azoles with only electron-poor aryl halides (Smith III et al., Tetrahedron Lett. 37:299-302 (1996)). This method is inefficient with electron-rich aryl halides (e.g., 4-bromo-t-butyl benzene, 3-bromo-methoxy benzene, 2-bromo-toluene) and electron neutral aryl halides (e.g., bromobenzene). Thus, a variety of potentially useful arylating compounds cannot be utilized in this method.
In another example, copper-mediated arylation of azoles was demonstrated to require high temperatures and polar solvents, thus increasing the complexity of the reaction conditions (Khan et al., J. Chem. Soc. C, 85-91 (1970)). In yet another example, N-aryl azoles have been shown to be synthesized from aryl boronic reagents using copper catalysts (Chan et al., Tet. Lett. 39:2933-2936 (1998); Lam et al., Tet. Lett. 39:2941-2944 (1998)).
In view of the above, a need exists for a general and efficient process of synthesizing N-aryl azoles and N-aryl imines from readily available arylating compounds. The discovery and implementation of such a method would simplify the preparation of commercially significant organic N-aryl azoles and N-aryl imines and would enhance the development of novel polymers and pharmacologically active compounds. The present invention is believed to be an answer to that need.